The modem reductionist approach to vaccine and therapy development has been pursued for a number of decades and attempts to focus only on those parts of pathogens or of cancer proteins which are relevant to the immune system. To date the performance of this approach has been relatively poor considering the vigorous research carried out and the number of effective vaccines and therapies that it has produced. This approach is still being actively pursued, however, despite its poor performance because vaccines developed using this approach are often extremely safe and because only by completely understanding the immune system can new vaccine strategies be developed.
One area that has benefited greatly from research efforts is knowledge about how the adaptive immune system operates and more specifically how T and B cells learn to recognise specific parts of pathogens and cancers. T cells are mainly involved in cell-mediated immunity whereas B cells are involved in the generation of antibody-mediated immunity. The two most important types of T cells involved in adaptive cellular immunity are αβ CD8+ cytotoxic T lymphocytes (CTL) and CD4+ T helper lymphocytes. CTL are important mediators of cellular immunity against many viruses, tumours, some bacteria and some parasites because they are able to kill infected cells directly and secrete various factors which can have powerful effects on the spread of infectious organisms. CTLs recognise epitopes derived from foreign intracellular proteins, which are 8-10 amino acids long and which are presented by class I major histocompatibility complex (MHC) molecules (in humans called human lymphocyte antigens—HLAs) (Jardetzky et al., 1991; Fremont et al., 1992; Rotzschke et al., 1990). T helper cells enhance and regulate CTL responses and are necessary for the establishment of long-lived memory CTL. They also inhibit infectious organisms by secreting cytokines such as IFN-γ. T helper cells recognise epitopes derived mostly from extracellular proteins which are 12-25 amino acids long and which are presented by class II MHC molecules (Chicz et al., 1993; Newcomb et al., 1993). B cells, or more specifically the antibodies they secrete, are important mediators in the control and clearance of mostly extracellular organisms. Antibodies recognise mainly conformational determinants on the surface of organisms, for example, although sometimes they may recognise short linear determinants.
Despite significant advances towards understanding how T and linear B cell epitopes are processed and presented to the immune system, the full potential of epitope-based vaccines has not been fully exploited. The main reason for this is the large number of different T cell epitopes, which have to be included into such vaccines to cover the extreme HLA polymorphism in the human population. The human HLA diversity is one of the main reasons why whole pathogen vaccines frequently provide better population coverage than subunit or peptide-based vaccine strategies. There is a range of epitope-based strategies though which have tried to solve this problem, e.g. peptide blends, peptide conjugates and polyepitope vaccines (ie comprising strings of multiple epitopes) (Dyall et al., 1995; Thomson et al., 1996; Thomson et al., 1998; Thomson et al., 1998). These approaches however will always be sub optimal not only because of the slow pace of epitope characterisation but also, because it is virtually impossible for them to cover every existing HLA polymorphism in the population. A number of strategies have sought to avoid both problems by not identifying epitopes and instead incorporating larger amounts of sequence information e.g., approaches using whole genes or proteins and approaches that mix multiple protein or gene sequences together. The proteins used by these strategies however sometimes still function and therefore can compromise vaccine safety e.g. whole cancer proteins. Alternative strategies have tried to improve the safety of vaccines by fragmenting the genes and expressing them either separately or as complex mixtures e.g., library DNA immunisation or by ligating such fragments back together. These approaches are still sub-optimal because they are too complex, generate poor levels of immunity, cannot guarantee that all proteins no longer function and/or that all fragments are present, which compromises substantially complete immunological coverage.
The lack of a safe and efficient vaccine strategy that can provide substantially complete immunological coverage is an important problem, especially when trying to develop vaccines against rapidly mutating and persistent viruses such as HIV and hepatitis C virus, because partial population coverage could allow vaccine-resistant pathogens to re-emerge in the future. Human immunodeficiency virus (HIV) is an RNA lentivirus virus approximately 9 kb in length, which infects CD4+ T cells, causing T cell decline and AIDS typically 3-8 years after infection. It is currently the most serious human viral infection, evidenced by the number of people currently infected with HIV or who have died from AIDS, estimated by the World Health Organisation (WHO) and UNAIDS in their AIDS epidemic update (December 1999) to be 33.6 and 16.3 million people, respectively. The spread of HIV is also now increasing fastest in areas of the world where over half of the human population reside, hence an effective vaccine is desperately needed to curb the spread of this epidemic. Despite the urgency, an effective vaccine for HIV is still some way off because of delays in defining the correlates of immune protection, lack of a suitable animal model, existence of up to 8 different subtypes of HIV and a high HIV mutation rate.
A significant amount of research has been carried out to try and develop a vaccine capable of generating neutralising antibody responses that can protect against field isolates of HIV. Despite these efforts, it is now clear that the variability, instability and inaccessibility of critical determinants on the HIV envelope protein will make it extremely difficult and perhaps impossible to develop such a vaccine (Kwong et al., 1998). The limited ability of antibodies to block HIV infection is also supported by the observation that development of AIDS correlates primarily with a reduction in CTL responsiveness to HIV and not to altered antibody levels (Ogg et al., 1998). Hence CTL-mediated and not antibody-mediated responses appear to be critical for maintaining the asymptomatic state in vivo. There is also some evidence to suggest that pre-existing HIV-specific CTL responses can block the establishment of a latent HIV infection. This evidence comes from a number of cases where individuals have generated HIV-specific CTL responses without becoming infected and appear to be protected from establishing latent HIV infections despite repeated virus exposure (Rowland-Jones et al., 1995; Parmiani 1998). Taken together, these observations suggest that a vaccine capable of generating a broad range of strong CTL responses may be able to stop individuals from becoming latently infected with HIV or at least allow infected individuals to remain asymptomatic for life. Virtually all of the candidate HIV vaccines developed to date have been derived from subtype B HIV proteins (western world subtype) whereas the majority of the HIV infections worldwide are caused by subtypes A/E or C (E and A are similar except in the envelop protein)(referred to as developing world subtypes). Hence existing candidate vaccines may not be suitable for the more common HIV subtypes. Recently, there has been some evidence that B subtype vaccines may be partially effective against other common HIV subtypes (Rowland-Jones et al., 1998). Accordingly, the desirability of a vaccine still remains, whose effectiveness is substantially complete against all isolates of all strains of HIV.